In the South African Journal of Child Health, Dempster and colleagues detail the case of a patient who was simultaneously diagnosed with 2 rare disorders: Alagille syndrome and von Willebrand disease.
A 17-year-old female patient presented with hypochromic anemia and splenomegaly. She had been diagnosed with Alagille syndrome in infancy due to having characteristic features of the disease, such as facial features, cholestasis, butterfly vertebrae, and peripheral pulmonary artery stenosis.
In addition, the patient also had a prior diagnosis of congenital von Willebrand disease, which was initially suspected because her mother had the disease. Blood tests measuring von Willebrand activity demonstrated that she had a severe form of the disease. She was prescribed desmopressin and has not had a single life-threatening bleeding episode.
“The underlying pathologies, combined with the observed splenomegaly and hypochromic anemia, raised concern of esophageal varices and potential life-threatening hemorrhage,” Dempster and colleagues wrote.
Read more about Alagille syndrome etiology
Liver function tests demonstrated normal bilirubin levels, with only mild transaminase derangement. Ultrasound revealed that the spleen measured 12.7 cm. There was no evidence of portal hypertension.
To exclude esophageal varices, the patient had an esophagogastroduodenoscopy, which revealed no visible varices. The scope did reveal a small hiatus hernia.
Her physicians reached a conclusion that the patient’s hypochromic anemia was due to menstrual bleeding, as the patient reported experiencing heavy menstrual bleeding for the last 7 days. In addition to desmopressin, the patient was prescribed oral iron supplementation. The patient’s anemia resolved after 4 months of oral iron supplementation.
Diagnosing von Willebrand Disease
The prevalence of von Willebrand disease has been much debated in recent years, since it is possible for patients of this disease to remain undiagnosed, particularly if they have a mild phenotype. Some epidemiological studies have placed the prevalence at as high as 1.3%.
Although this disease is thought to affect both men and women equally, it tends to be diagnosed more frequently in women due to gynecological-related bleeding. Compared to hemophilia, the symptoms of bleeding tend to be milder.
“Given the heterogeneity of the disease that is observed sometimes within the same family or even in the same patient throughout his/her lifetime, [von Willebrand disease] has been and remains to this day a complex entity to diagnose and to manage, partially explaining the difference between prevalence and actually diagnosed patients,” Denis and colleagues wrote in Blood.
The best clue for the presence of this disease is a family history of heavy bleeding. The challenge this presents is that bleeding is subjective, and menstrual bleeding, in particular, remains a taboo subject among some individuals.
Around half of female patients are not diagnosed with the disease until age 12, probably only when heavy menarche is noticed. In contrast, most male patients with this disease are diagnosed by age 10.
“Delayed diagnosis may result in missed treatment opportunities and increased morbidity (both medical and psychological),” Denis et al wrote. “It is thus important to increase knowledge and awareness of [von Willebrand disease] among (general) clinicians and the public.”
In the case of the patient described, she received desmopressin, which prevented her from developing any serious bleeding episodes. Desmopressin has been the primary drug for managing von Willebrand disease for the last 3 decades; it was only in the last decade or so that recombinant von Willebrand factor concentrate became available for managing the disease.
Desmopressin has a number of advantages: it is relatively cheap, can be administered via various routes, and is without risk of transmittable disease. In 80% of cases, it achieves adequate levels of von Willebrand factor and factor VIII. The main concern that physicians have regarding desmopressin is that it may induce reduced responsiveness when used repetitively.
Managing Patients With Rare Comorbidities
In the case of the patient described, she was diagnosed with both Alagille syndrome and von Willebrand disease early in life. This presented her physicians with the unique challenge of monitoring the progress of both diseases, as well as ways in which one disease might aggravate the other. A main feature of Alagille syndrome is worsening liver disease.
“Hepatic disease is the highest cause of morbidity in [Alagille syndrome] and ranges from mild biochemical abnormalities to end-stage liver disease, which is seen in up to 15% of cases,” Dempster and colleagues wrote. “For patients who present with liver disease in infancy, 20-30% will develop intractable portal hypertension, cirrhosis or synthetic liver failure.”
Read more about Alagille syndrome complications
When the patient presented with both anemia and splenomegaly, the immediate concern of her physicians was to rule out esophageal varices, which can be life-threatening. Her risk of developing esophageal varices was high for two reasons: first, Alagille syndrome predisposes her to develop cirrhosis, which is a significant risk factor for varices; second, von Willebrand disease can cause angiodysplasia, which can result in gastrointestinal bleeding.
Fortunately, in the case of this patient, no varices were detected and she was managed conservatively. This case study highlights the need for physicians to be extra vigilant when managing patients with existing comorbidities, especially if they are rare.
Dempster MJ, Jacobson BF, Walabh B. Alagille syndrome and hereditary von Willebrand disease: a rare co-occurrence. S Afr J Child Health. 2021;15(3):175-178. doi:10.7196/SAJCH.2021.v15.i3.1820
Denis CV, Susen S, Lenting PJ. von Willebrand disease: what does the future hold? Blood. 2021;137(17):2299-2306. doi:10.1182/blood.2020008501